Smarter drugs emerging in pancreatic cancer therapy

Annals of Oncology

Volumn 25, Issue 7, 2014, Pages 1260-1270

  Kleger, A ^a   Perkhofer, L ^a   Seufferlein, Thomas ^a  

^a UNIVERSITY OF ULM   (Germany)

Author keywords

Advanced disease; Cancer; Pancreatic ductal adenocarcinoma; Targeted therapies; Treatment

Indexed keywords

AFLIBERCEPT; AXITINIB; BEVACIZUMAB; CABOZANTINIB; CETUXIMAB; CIXUTUMUMAB; CONATUMUMAB; DACTOLISIB; ERLOTINIB; EVEROLIMUS; FLUOROURACIL; FOLINIC ACID; GANITUMAB; GEMCITABINE; IRINOTECAN; LAPATINIB; MARIMASTAT; MATUZUMAB; NIMOTUZUMAB; OXALIPLATIN; PACLITAXEL; PANITUMUMAB; PLACEBO; SELUMETINIB; SONIDEGIB; SORAFENIB; SUNITINIB; TIPIFARNIB; TRAMETINIB; UNINDEXED DRUG; ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR; FARNESYL TRANS TRANSFERASE;

ANTIANGIOGENIC ACTIVITY; AUTOPHAGY; CHEMORADIOTHERAPY; CONJUGATION; DRUG WITHDRAWAL; GENE MUTATION; HUMAN; INDUCTION CHEMOTHERAPY; INFLAMMATION; LOW DRUG DOSE; MAINTENANCE CHEMOTHERAPY; MOLECULARLY TARGETED THERAPY; MONOTHERAPY; ONCOGENE K RAS; OVERALL SURVIVAL; PANCREAS ADENOCARCINOMA; PANCREATIC NEUROENDOCRINE TUMOR; PANCREATIC STELLATE CELL; PERSONALIZED MEDICINE; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; RASH; REVIEW; STROMA; UNSPECIFIED SIDE EFFECT; AGED; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; MULTIMODALITY CANCER THERAPY; PANCREATIC NEOPLASMS;

AGED; ANGIOGENESIS INHIBITORS; ANTINEOPLASTIC AGENTS; AUTOPHAGY; COMBINED MODALITY THERAPY; FARNESYLTRANSTRANSFERASE; HUMANS; PANCREATIC NEOPLASMS; RECEPTOR, EPIDERMAL GROWTH FACTOR;

EID: 84903714441     PISSN: 09237534     EISSN: 15698041     Source Type: Journal    
DOI: 10.1093/annonc/mdu013     Document Type: Review

References (158)

1. Jemal A, Siegel R, Xu J et al. Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277-300.
2. Haberland J, Bertz J, Wolf U et al. German cancer statistics 2004. BMC Cancer 2010; 10: 52.
3. Matano E, Tagliaferri P, Libroia A et al. Gemcitabine combined with continuous infusion 5-fluorouracil in advanced and symptomatic pancreatic cancer: a clinical benefit-oriented phase II study. Br J Cancer 2000; 82: 1772-1775.
4. Vaccaro V, Sperduti I, Milella M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 365: 768-769; author reply 769.
5. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol 2013; 31: 23-29.
6. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817-1825.
7. Von Hoff DD, Ervin T, Arena FP et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691-1703.
8. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960-1966.
9. Kang SP, Saif MW. Optimal second line treatment options for gemcitabine refractory advanced pancreatic cancer patients. Can we establish standard of care with available data? J Pancreas 2008; 9: 83-90.
10. Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239-246.
11. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735-742.
12. Walsh N, Kennedy S, Larkin A et al. EGFR and HER2 inhibition in pancreatic cancer. Invest New Drugs 2012; 31: 558-566.
13. Valsecchi ME, McDonald M, Brody JR et al. Epidermal growth factor receptor and insulin-like growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma. Cancer 2012; 118: 3484-3493.
14. Einama T, Ueda S, Tsuda H et al. Membranous and cytoplasmic expression of epidermal growth factor receptor in metastatic pancreatic ductal adenocarcinoma. Exp Ther Med 2012; 3: 931-936.
15. Ardito CM, Gruner BM, Takeuchi KK et al. EGF receptor is required for KRASinduced pancreatic tumorigenesis. Cancer Cell 2012; 22: 304-317.
16. Navas C, Hernandez-Porras I, Schuhmacher AJ et al. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 2012; 22: 318-330.
17. Kullmann F, Hollerbach S, Dollinger MM et al. Cetuximab plus gemcitabine/ oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study. Br J Cancer 2009; 100: 1032-1036.
18. Hammel P, Huguet F, van Laethem J-L et al. Comparison of chemoradiotherapy and chemotherapy in patients with a locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: final results of the international phase III LAP 07 study. ASCO Annual Meeting, 2013. Abstract LBA4003.
19. Strumberg D, Schultheis B, Ebert MP et al. Phase II, randomized, double-blind placebo-controlled trial of nimotuzumab plus gemcitabine compared with gemcitabine alone in patients ( pts) with advanced pancreatic cancer (PC). J Clin Oncol 2013: 31 (suppl; abstr 4009).
20. NCT00561990. A Randomized, Multicenter, Phase IIB/IIIA Study of Gemcitabine and the Monoclonal Antibody Nimotuzumab (OSAG 101) versus Gemcitabine and Placebo for the Treatment of Chemotherapy-naive Patients with Locally Advanced or Metastatic Pancreatic Cancer. 2007.
21. Graeven U, Kremer B, Sudhoff T et al. Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer. Br J Cancer 2006; 94: 1293-1299.
22. Kim GP, Foster NR, Salim M et al. Randomized phase II trial of panitumumab (P), erlotinib (E) and gemcitabine (G) versus erlotinib-gemcitabine in patients with untreated, metastatic pancreatic adenocarcinoma. J Clin Oncol 2011; (suppl 4):abstr 238.
23. Philip PA, Benedetti J, Corless CL et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 2010; 28: 3605-3610.
24. Boeck S, Jung A, Laubender RP et al. EGFR pathway biomarkers in erlotinibtreated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer 2013; 108:469-476.
25. Van Cutsem E, Kohne CH, Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360:1408-1417.
26. Bokemeyer C, Bondarenko I, Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009; 27: 663-671.
27. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337-345.
28. Stintzing S, Kapaun C, Laubender RP et al. Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway:results from a randomized trial of the GERMAN AIO CRC Study Group. Int J Cancer 2013; 132: 236-245.
29. Bergmann U, Funatomi H, Yokoyama M et al. Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res 1995; 55: 2007-2011.
30. Rieder S, Michalski CW, Friess H et al. Insulin-like growth factor signaling as a therapeutic target in pancreatic cancer. Anticancer Agents Med Chem 2011; 11:427-433.
31. Liao X, Morikawa T, Lochhead P et al. Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review. Clin Cancer Res 2012; 18:2257-2268.
32. Saini KS, Loi S, de Azambuja E et al. Targeting the PI3K/AKT/mTOR and Raf/ MEK/ERK pathways in the treatment of breast cancer. Cancer Treat Rev 2013; 39: 935-946.
33. Liao X, Lochhead P, Nishihara R et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012; 367: 1596-1606.
34. Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: crosstalk and compensation. Trends Biochem Sci 2011; 36: 320-328.
35. Liu P, Cheng H, Roberts TM et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8: 627-644.
36. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9: 550-562.
37. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006; 7: 606-619.
38. Bader AG, Kang S, Zhao L et al. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 2005; 5: 921-929.
39. Pal SK, Reckamp K, Yu H et al. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 2010; 19: 1355-1366.
40. Samuels Y, Wang Z, Bardelli A et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304: 554.
41. Philip PA, Goldman BH, Ramanathan RK et al. Dual blockade of epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) signaling in metastatic pancreatic cancer: Phase I/randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG-0727). J Clin Oncol 2012; 30 (suppl; abstr 4019).
42. Kindler HL, Richards DA, Stephenson J et al. A placebo-controlled, randomized phase II study of conatumumab (C) or AMG 479 (A) or placebo (P) plus gemcitabine (G) in patients ( pts) with metastatic pancreatic cancer (mPC). J Clin Oncol 2010; 28 (15s suppl; abstr 4035).
43. NCT01028495. A Safety and Efficacy Study of RX-0201 Plus Gemcitabine in Metastatic Pancreatic Cancer. ClinicalTrials.gov 2013.
44. Venkannagari S, Fiskus W, Peth K et al. Superior efficacy of co-treatment with dual PI3K/mTOR inhibitor NVP-BEZ235 and pan-histone deacetylase inhibitor against human pancreatic cancer. Oncotarget 2012; 3: 1416-1427.
45. NCT01138085. A Phase I Dose Escalation Open-Label Safety and Pharmacokinetics Study to Determine the Recommended Phase II Dose of GSK1120212 Dosed in Combination With GSK2141795 in Subjects With Solid Tumors (Part 1) and in Subjects With Pancreatic Cancer, Endometrial Cancer or Colorectal Cancer. 2010.
46. Yim KL. Everolimus and mTOR inhibition in pancreatic neuroendocrine tumors. Cancer Manag Res 2012; 4: 207-214.
47. Wolpin BM, Hezel AF, Abrams T et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol 2009; 27:193-198.
48. NCT00640978. Phase II Study of Erlotinib and RAD001 (Everolimus) in Patients With Previously Treated Advanced Pancreatic Cancer. ClinicalTrials. gov 2012.
49. Singh BN, Kumar D, Shankar S et al. Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem Pharmacol 2012; 84: 1154-1163.
50. Hermann PC, Huber SL, Herrler T et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007; 1: 313-323.
51. Mueller MT, Hermann PC, Witthauer J et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology 2009; 137: 1102-1113.
52. Hermann PC, Huber SL, Heeschen C. Metastatic cancer stem cells: a new target for anti-cancer therapy? Cell Cycle 2008; 7: 188-193.
53. Li C, Wu JJ, Hynes M et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 2011; 141: 2218-2227, e2215.
54. Gherardi E, Birchmeier W, Birchmeier C et al. Targeting MET in cancer: rationale and progress. Nat Rev Cancer 2012; 12: 89-103.
55. NCT01466036. An Open-Label, Phase II Study of Cabozantinib (XL184) in Advanced Pancreatic Neuroendocrine and Carcinoid Tumors. 2011.
56. Neuzillet C, Hammel P, Tijeras-Raballand A et al. Targeting the Ras-ERK pathway in pancreatic adenocarcinoma. Cancer Metastasis Rev 2012; 32: 147-162.
57. Tolcher AW, Bendell JC, Papadopoulos PK et al. A phase Ib study of the MEK inhibitor GSK1120212 combined with gemcitabine in patients with solid tumors:Interim results. J Clin Oncol 2011; 29 (suppl 4; abstr 278).
58. NCT01016483. Trial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer. ClinicalTrials.gov 2013.
59. NCT01231581. A Randomized, Double-Blind Placebo-Controlled Phase II Study of the MEK Inhibitor GSK1120212 Plus Gemcitabine vs Placebo Plus Gemcitabine in Subjects With Metastatic Pancreatic Cancer. ClinicalTrials.gov 2013.
60. Larbouret C, Gaborit N, Chardes T et al. In pancreatic carcinoma, dual EGFR/ HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' down-regulation and dimers' disruption. Neoplasia 2012; 14: 121-130.
61. Walters DM, Lindberg JM, Adair SJ et al. Inhibition of the growth of patientderived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/ HER2 inhibitor lapatinib. Neoplasia 2013; 15: 143-155.
62. Hezel AF, Kimmelman AC, Stanger BZ Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006; 20(10): 1218-1249.
63. Kordes S, Richel DJ, Klumpen HJ et al. A phase I/II, non-randomized, feasibility/ safety and efficacy study of the combination of everolimus, cetuximab and capecitabine in patients with advanced pancreatic cancer. Invest New Drugs 2013; 31: 85-91.
64. Ko AH, LoConte NK, Kantoff E et al. A phase Ib trial of FOLFIRINOX plus saridegib, an oral hedgehog (Hh) inhibitor, in pts with advanced pancreatic cancer (PDAC). J Clin Oncol 2012; 30 (suppl; abstr 3105).
65. Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 1995; 36: 127-137.
66. Seo Y, Baba H, Fukuda T et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000; 88: 2239-2245.
67. Kindler HL, Niedzwiecki D, Hollis D et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 2010; 28: 3617-3622.
68. Van Cutsem E, Vervenne WL, Bennouna J et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 2009; 27: 2231-2237.
69. Kindler HL, Ioka T, Richel DJ et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a doubleblind randomised phase 3 study. Lancet Oncol 2011; 12: 256-262.
70. Gaya A, Tse V. A preclinical and clinical review of aflibercept for the management of cancer. Cancer Treat Rev 2012; 38: 484-493.
71. Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 2000; 351: 289-305.
72. Wilhelm SM, Carter C, Tang LY et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64:7099-7109.
73. Siu LL, Awada A, Takimoto CH et al. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 2006; 12: 144-151.
74. Kindler HL, Wroblewski K, Wallace JA et al. Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Invest New Drugs 2012; 30: 382-386.
75. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007; 25: 884-896.
76. Gan HK, Seruga B, Knox JJ. Sunitinib in solid tumors. Expert Opin Investig Drugs 2009; 18: 821-834.
77. Hartmann JT, Kanz L. Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch Dermatol 2008; 144: 1525-1526.
78. Mendel DB, Laird AD, Xin X et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/ pharmacodynamic relationship. Clin Cancer Res 2003; 9: 327-337.
79. O'Farrell AM, Abrams TJ, Yuen HA et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003; 101:3597-3605.
80. Olson P, Chu GC, Perry SR et al. Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma. Proc Natl Acad Sci USA 2011; 108: E1275-E1284.
81. Demetri GD, van Oosterom AT, Garrett CR et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368: 1329-1338.
82. O'Reilly EM, Niedzwiecki D, Hall M et al. A Cancer and Leukemia Group B phase II study of sunitinib malate in patients with previously treated metastatic pancreatic adenocarcinoma (CALGB 80603). Oncologist 2010; 15: 1310-1319.
83. Richly H, Maute L, Heil G et al. Prospective randomized phase II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. J Clin Oncol 2013; 31 (suppl; abstr 4035).
84. Reni M, Cereda S, Milella M et al. Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: a phase II randomised trial. Eur J Cancer 2013; 49: 3609-3615.
85. Olive KP, Jacobetz MA, Davidson CJ et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457-1461.
86. Catenacci DVT, Bahary N, Nattam SR et al. Final analysis of a phase IB/ randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients ( pts) with metastatic pancreatic cancer (PC): A University of Chicago phase II consortium study. J Clin Oncol 2013; 31 (suppl; abstr 4012).
87. NCT01487785. A Phase Ib, Open-label, Multicenter, Dose-escalation, Safety and Tolerability Study of LDE225 in Combination With Gemcitabine in Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma. 2011.
88. Jones S, Zhang X, Parsons DW et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321:1801-1806.
89. Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol 1999; 17: 3631-3652.
90. End DW, Smets G, Todd AV et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001; 61: 131-137.
91. Van Cutsem E, van de Velde H, Karasek P et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004; 22: 1430-1438.
92. Chandra A, Grecco HE, Pisupati V et al. The GDI-like solubilizing factor PDEdelta sustains the spatial organization and signalling of Ras family proteins. Nat Cell Biol 2012; 14: 148-158.
93. Zimmermann G, Papke B, Ismail S et al. Small molecule inhibition of the KRASPDEdelta interaction impairs oncogenic KRAS signalling. Nature 2013; 497:638-642.
94. Erkan M, Hausmann S, Michalski CW et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 2012; 9: 454-467.
95. Erkan M, Reiser-Erkan C, Michalski CW et al. The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance. Curr Mol Med 2012; 12: 288-303.
96. Erkan M, Adler G, Apte MV et al. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 2012; 61: 172-178.
97. Erkan M, Michalski CW, Rieder S et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 2008; 6: 1155-1161.
98. Bachem MG, Schneider E, Gross H et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115: 421-432.
99. Xu Z, Vonlaufen A, Phillips PA et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 2010; 177: 2585-2596.
100. Erkan M, Reiser-Erkan C, Michalski CW et al. Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia 2009; 11: 497-508.
101. Lu X, Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 2010; 16: 5928-5935.
102. Krantz SB, Shields MA, Dangi-Garimella S et al. MT1-MMP cooperates with Kras (G12D) to promote pancreatic fibrosis through increased TGF-beta signaling. Mol Cancer Res 2011; 9: 1294-1304.
103. Sato H, Takino T, Okada Y et al. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 1994; 370: 61-65.
104. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 161-174.
105. He XJ, Jiang XT, Ma YY et al. REG4 contributes to the invasiveness of pancreatic cancer by upregulating MMP-7 and MMP-9. Cancer Sci 2012; 103:2082-2091.
106. Shchors K, Nozawa H, Xu J et al. Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis. Oncogene 2013; 32: 502-513.
107. Bramhall SR, Rosemurgy A, Brown PD et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001; 19: 3447-3455.
108. Bramhall SR, Schulz J, Nemunaitis J et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002; 87: 161-167.
109. Moore MJ, Hamm J, Dancey J et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003; 21:3296-3302.
110. Low JA, de Sauvage FJ. Clinical experience with Hedgehog pathway inhibitors. J Clin Oncol 2010; 28: 5321-5326.
111. Ingham PW, McMahon AP. Hedgehog signaling in animal development:paradigms and principles. Genes Dev 2001; 15: 3059-3087.
112. Bailey JM, Swanson BJ, Hamada T et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 2008; 14: 5995-6004.
113. Hidalgo M, Maitra A. The hedgehog pathway and pancreatic cancer. N Engl J Med 2009; 361: 2094-2096.
114. Duman-Scheel M, Weng L, Xin S et al. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 2002; 417: 299-304.
115. Pola R, Ling LE, Silver M et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 2001; 7: 706-711.
116. Feldmann G, Habbe N, Dhara S et al. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 2008; 57:1420-1430.
117. Lang M. Infinity Pharma halts pancreatic cancer trial. 2013. http://www. bizjournals.com/boston/blog/mass-high-tech/2012/01/infinity-pharma-haltspancreatic- cancer-trial.html.
118. Catenacci DVT, Bahary N, Edelman MJ et al. A phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients ( pts) with metastatic pancreatic cancer (PC): Interim analysis of a University of Chicago phase II consortium study. J Clin Oncol 2012; 30 (suppl; abstr 4022).
119. NCT01485744. A Phase 1b Clinical Trial of LDE225 in Combination With Fluorouracil, Leucovorin, Oxaliplatin and Irinotecan (FOLFIRINOX) in Previously Untreated Locally Advanced or Metastatic Pancreatic Adenocarcinoma, With an Expansion Cohort at the Recommended Phase 2 Dos.: ClinicalTrials.gov 2013.
120. Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res 2011; 71: 5057-5061.
121. Buonamici S, Williams J, Morrissey M et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med 2010; 2: 51ra70.
122. Dijkgraaf GJ, Alicke B, Weinmann L et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res 2011; 71: 435-444.
123. Kotowski A, Ma WW. Emerging therapies in pancreas cancer. J Gastrointest Oncol 2011; 2: 93-103.
124. Neuzillet C, Tijeras-Raballand A, Cros J et al. Stromal expression of SPARC in pancreatic adenocarcinoma. Cancer Metastasis Rev 2013; 32: 585-602.
125. Miyoshi K, Sato N, Ohuchida K et al. SPARC mRNA expression as a prognostic marker for pancreatic adenocarcinoma patients. Anticancer Res 2010; 30:867-871.
126. Neesse A, Frese KK, Chan DS et al. SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut 2013; gutjnl-2013-305559.
127. Von Hoff DD, Ervin TJ, Arena FP et al. Randomized phase III study of weekly nabpaclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). J Clin Oncol 2012; 30 (suppl 34; abstr LBA148).
128. NCT01010945. A Phase IB Study of Erlotinib in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Previously Untreated Advanced Pancreatic Cancer. ClinicalTrials.gov 2013.
129. NCT01461915. A Randomized Phase II Open Label Study to Assess the Efficacy & Safety of Gemcitabine + Abraxane® With or Without ODSH (2-0, 30 Desulfated Heparin) as First Line Treatment of Metastatic Pancreatic Cancer. ClinicalTrials.gov 2013.
130. Casu B, Vlodavsky I, Sanderson RD. Non-anticoagulant heparins and inhibition of cancer. Pathophysiol Haemost Thromb 2008; 36: 195-203.
131. NCT00377936. A Controlled, Randomized, Open Label Phase II Trial to Evaluate Safety and Efficacy of a 1st Line Combination Treatment With Weekly Infusions of Gemcitabine and Twice Weekly Administration of Lipid Complexed Paclitaxel (EndoTAG-1) in Three Dose Levels Compared With Gemcitabine Monotherapy in Patients With Measurable Locally Advanced and/or Metastatic Adenocarcinoma of the Pancreas. ClinicalTrials.gov 2008.
132. McDonald A, Yang A. TH-302 Phase IIb Clinical Results In First-Line Pancreatic Cancer. 2013. http://seekingalpha.com/article/536581-threshold-pharmaceuticalsth-302-phase-iib-clinical-results-in-first-line-pancreatic-cancer.
133. Ryan DP, Reddy SG, Bahary N et al. TH-302 plus gemcitabine (G + T) versus gemcitabine (G) in patients with previously untreated advanced pancreatic cancer (PAC). J Clin Oncol 2012; 30 (suppl 34; abstr 325).
134. Schelman WR, Borad MJ, Chiorean EG et al. Phase I/II study of TH-302 in combination with gemcitabine in patients with solid tumors including advanced pancreatic cancer. J Clin Oncol 2010; 28 (suppl; abstr e13519).
135. Clark CE, Hingorani SR, Mick R et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007; 67: 9518-9527.
136. Beatty GL, Chiorean EG, Fishman MP et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011; 331: 1612-1616.
137. Bennett SR, Carbone FR, Karamalis F et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 1998; 393: 478-480.
138. van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol 2000; 67:2-17.
139. NCT01456585. Phase 1 Study of Preoperative Gemcitabine Plus CP-870,893 Followed by Addition of CP-870,893 to Standard -Of-care Adjuvant Chemoradiation for Patient With Newly Diagnosed Resectable Pancreatic Carcinoma. ClinicalTrials.gov 2013.
140. Kang R, Tang D. Autophagy in pancreatic cancer pathogenesis and treatment. Am J Cancer Res 2012; 2: 383-396.
141. Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol 2010; 12: 823-830.
142. Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010; 40: 280-293.
143. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132:27-42.
144. Amaravadi RK, Yu D, Lum JJ et al. Autophagy inhibition enhances therapyinduced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117: 326-336.
145. Fujii S, Mitsunaga S, Yamazaki M et al. Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci 2008; 99:1813-1819.
146. Yang S, Wang X, Contino G et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev 2011; 25: 717-729.
147. Donadelli M, Dando I, Zaniboni T et al. Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis 2011; 2: e152.
148. NCT01506973. A Phase I/II/Pharmacodynamic Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane to Inhibit Autophagy in Pancreatic Cancer. ClinicalTrials.gov 2012.
149. Loehrer PJ, Feng Y, Cardenes H et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011; 29: 4105-4112.
150. Small W, Mulcahy MF, Rademaker A et al. Phase II trial of full-dose gemcitabine and bevacizumab in combination with attenuated three-dimensional conformal radiotherapy in patients with localized pancreatic cancer. Int J Radiat Oncol Biol Phys 2011; 80: 476-482.
151. Crane CH, Varadhachary GR, Yordy JS et al. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol 2011; 29:3037-3043.
152. Ramanathan RK, Barrett M, Weiss GJ et al. Phase II study of therapy selected by molecular profiling in patients with previously treated metastatic pancreatic cancer. A study of the stand up to cancer (SU2C) consortium. In Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research, Chicago, IL, 31 March-4 April 2012. Philadelphia, (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-221. doi:1538-7445.AM2012-LB-221.
153. Villarroel MC, Rajeshkumar NV, Garrido-Laguna I et al. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther 2011; 10: 3-8.
154. Hammel P, Mornex F, Deplanque G et al. Oral tyrosine kinase inhibitor masitinib in combination with gemcitabine in patients with advanced pancreatic cancer: A multicenter phase II study. J Clin Oncol 2009; 27 (15s suppl; abstr 4617).
155. SA AS. AB Science reports phase 3 study results of masitinib in combination with Gemzar(R) for treatment of pancreatic cancer. 2013. http://www.marketwatch. com/story/ab-science-reports-phase-3-study-results-of-masitinib-in-combinationwith- gemzarr-for-treatment-of-pancreatic-cancer-2012-10-30.
156. Deplanque G, Demarchi M, Hebbar M et al. Masitinib in nonresectable pancreatic cancer: Results of a phase III randomized placebo-controlled trial. J Clin Oncol 2012 (abstract 158).
157. Lonardo E, Frias-Aldeguer J, Hermann PC et al. Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle 2012; 11: 1282-1290.
158. Lonardo E, Hermann PC, Mueller MT et al. Nodal/activin signaling drives selfrenewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 2011; 9: 433-446.